The objective of this research is to determine the molecular basis of Alstrom Syndrome, a recessive disease characterized by conditions that are frequently observed in the general population. These include progressive aural and retinal degeneration, obesity, and Type II diabetes. Affected individuals normally die of heart disease or renal insufficiency in their second to fourth decade of life. Although it is unlikely that mutations within the Alstrom gene play a major role in any of these common complex disease traits, the real value of identifying the Alstrm gene lies in the access it may provide to novel metabolic and regulatory pathways involved in neurosensory disease, obesity, type II diabetes, and related disorders. The Alstrom gene was localized to Chr. 2p13 by homozygosity mapping in a large French Acadian kindred. With the addition of results from two point linkage analysis of nine sporadic nuclear families segregating for the syndrome, the reported peak maximum lod score has increased from 3.84 to 5.75 (q = 0.00) at D2S327. Currently the minimal region containing the Alstrom gene is 6.1 cM in size. The specific aims of this proposal include: (1) to narrow the genetic region continuing Alstrom to approximately 1 cM by identifying recombinant chromosomes in families segregating for Alstrom Syndrome; (2) to construct a high resolution, high density genetic map of candidate genes and anonymous markers of the Alstrom region with 1 marker every 1-200 kb; (3) to construct a physical P1 and BAC contig of the region; and (4) to identify the mutant transcript responsible for Alstrom Syndrome by examining ESTs and corresponding full length cDNAs expressed in appropriate tissues and by cDNA selection. The characteristics of deafness, blindness, and obesity have been described in a number of childhood syndromes, suggesting a basic defect in common developmental pathways. Locating and identifying the gene and the molecular defect causing Alstrom may give us insight into what those pathways are. Study of the gene product, its pattern of expression and how it impacts on other genes will lead to a better understanding of how normal biological pathways function.